SXR as a Therapeutic Target in Drug Resistant Cancer

描述：(申请人提供) 类固醇和异源生物受体(SXR)是新近发现的一个成员。 核受体家族的蛋白质；SXR与RXR异二聚化以 激活基因转录。已知的激活SXR的配体包括几个 类固醇如雌二醇、黄体酮和皮质酮，以及药物如 利福平、克霉唑和硝苯地平。在这方面工作的基本原理 建议是基于我们的观察：a)紫杉醇，而不是紫杉醇，是一种 SXR的有效激活剂；b)SXR是MDR1的转录激活剂，并 细胞色素P450 3A4在人体组织中的表达；c)细胞 与已知的SXR激活剂，如紫杉醇，显示快速诱导PGP 和CYP3A4的表达导致显著增加的 化疗药物外流和代谢失活；以及d)SXR、Pgp和 CYP3A4在多种人类肿瘤中都有不同程度的表达。我们的数据显示 SXR可能是多重耐药表型的部分原因 通过快速而短暂地诱导药物运输所需的基因 和新陈代谢清除。我们假设SXR是一个重要的决定因素 通过瞬时诱导药物所需的基因来改变MDR表型 排毒，以及那些旨在阻止 SXR的激活可能抑制耐药的发生。在测试我们的 假设，我们将对信号通路有更好的理解 CYP3A4、mdr1和其他耐药相关基因的上游，以及 阐明这些基因通过SXR的内在诱导性是否是 癌症治疗失败的重要机制。此外，这项工作 将确定SXR基因的表达是否升高 在人类肿瘤中相对于邻近的正常组织。如果我们的总体假设 被证实，不是SXR配体的新试剂或阻断 SXR的激活，将扼杀诱导性药物的出现 SXR过表达肿瘤患者的耐药性。

DESCRIPTION: (provided by applicant) The Steroid and Xenobiotic Receptor (SXR) is a recently-identified member of the nuclear receptor family of proteins; SXR heterodimerizes with RXR to activate gene transcription. Ligands known to activate SXR include several steroids such as estradiol, progesterone and corticosterone, and drugs such as rifampicin, clotrimazole and nifedipine. The rationale for work in this proposal is based on our observations that: a) taxol, but not taxotere, is a potent activator of SXR; b) SXR is a transcriptional activator of MDR1 and cytochrome P450 3A4 (CYP3A4) expression in human tissues; c) cells treated with known activators of SXR, such as taxol, exhibit a rapid induction of Pgp and CYP3A4 expression resulting in significantly increased rates of chemotherapeutic drug efflux and metabolic inactivation; and d) SXR, Pgp, and CYP3A4 are variably expressed in a range of human tumors. Our data suggests that SXR may be responsible in part for the multiple drug resistance phenotype through a rapid and transient induction of genes required for drug transport and metabolic clearance. We hypothesize that SXR is an important determinant of the MDR phenotype by transiently inducing the genes required for drug detoxification, and that new compounds or strategies designed to block activation of SXR may inhibit the emergence of drug resistance. In testing our hypothesis, we will gain a better understanding of the signaling pathway upstream of CYP3A4, MDR1, and other drug resistance-associated genes, and elucidate whether the inherent inducibility of these genes through SXR is an important mechanism of treatment failure in cancer. Furthermore, the work performed in this proposal will determine if SXR gene expression is elevated in human tumors relative to adjacent normal tissues. If our overall hypothesis is confirmed, new agents which are not ligands for SXR or drugs which block the activation of SXR, will abrogate the emergence of inducible drug resistance in patients with SXR-overexpressing tumors.